Hypotensive Lipid And Timolol Compositions And Methods Of Using Same

ABSTRACT

New compositions for and methods of treating ocular hypertension provide for effective treatment of ocular hypertension often using reduced concentrations of active components. Such compositions include a timolol component and a hypotensive lipid component. The present compositions and methods are relatively straightforward, can be easily produced, for example, using conventional manufacturing techniques, and can be easily and conveniently practiced, for example, using application or administration techniques or methodologies which are substantially similar to those employed with prior compositions used to treat ocular hypertension.

RELATED APPLICATION

This application claims the benefit of U.S. provisional application Ser.No. 60/294,845 filed May 31, 2001, the disclosure of which isincorporated in its entirety herein by reference.

BACKGROUND OF THE INVENTION

The present invention relates to compositions useful for and methods oftreating ocular hypertension. More particularly, the invention relatesto such compositions and methods which effectively treat ocularhypertension, for example, reduce or at least maintain intraocularpressure and preferably provide enhanced benefits and/or have reducedside effects relative to other compositions and methods.

Ocular hypotensive agents are useful in the treatment of a number ofvarious ocular hypertensive conditions, such as post-surgical andpost-laser trabeculectomy ocular hypertensive episodes, glaucoma, and aspresurgical adjuncts.

Glaucoma is a disease of the eye characterized by increased intraocularpressure. On the basis of its etiology, glaucoma has been classified asprimary or secondary. For example, primary glaucoma in adults(congenital glaucoma) may be either open-angle or acute or chronicangle-closure. Secondary glaucoma results from pre-existing oculardiseases such as uveitis, intraocular tumor or an enlarged cataract.

The underlying causes of primary glaucoma are not yet known. Theincreased intraocular tension is due to the obstruction of aqueous humoroutflow. In chronic open-angle glaucoma, the anterior chamber and itsanatomic structures appear normal, but drainage of the aqueous humor isimpeded. In acute or chronic angle closure glaucoma, the anteriorchamber is shallow, the filtration angle is narrowed, and the iris mayobstruct the trabecular meshwork at the entrance of the canal ofSchlemm. Dilation of the pupil may push the root of the iris forwardagainst the angle, and may produce pupillary block and thus precipitatean acute attack. Eyes with narrow anterior chamber angles arepredisposed to acute angle-closure glaucoma attacks of various degreesof severity.

Secondary glaucoma is caused by any interference with the flow ofaqueous humor from the posterior chamber into the anterior chamber andsubsequently, into the canal of Schlemm. Inflammatory disease of theanterior segment may prevent aqueous escape by causing completeposterior synechia in iris bombe and may plug the drainage channel withexudates. Other common causes are intraocular tumors, enlargedcataracts, central retinal vein occlusion, trauma to the eye, operativeprocedures and intraocular hemorrhage.

Considering ail types together, glaucoma occurs in about 2% of allpersons over the age of 40 and may be asymptotic for years beforeprogressing to rapid loss of vision. In cases where surgery is notindicated, topical b-adrenoreceptor antagonists have traditionally beenthe drugs of choice for treating glaucoma.

Prostaglandins were earlier regarded as potent ocular hypertensives;however, evidence accumulated in the last two decades shows that someprostaglandins are highly effective ocular hypotensive agents and areideally suited for the long-term medical management of glaucoma. (See,for example, Starr, M. S. Exp. Eye Res. 1971, 11, pp. 170-177; Bito, L.Z. Biological Protection with Prostaglandins Cohen, M. M., ed., BocaRaton, Fla., CRC Press Inc., 1985, pp. 231-252; and Bito, L. Z., AppliedPharmacology in the Medical Treatment of Glaucomas Drance, S. M. andNeufeld, A. H. eds., New York, Grune & Stratton, 1984, pp. 477-505).Such prostaglandins include PGF_(2a), PGF_(1a), PGE₂, and certainlipid-soluble esters, such as C₁ to C₅ alkyl esters, e.g. 1-isopropylester, of such compounds.

In the U.S. Pat. No. 4,599,353 certain prostaglandins, in particularPGE₂ and PGF_(2a) and the C₁ to C₅ alkyl esters of the latter compound,were reported to possess ocular hypotensive activity and wererecommended for use in glaucoma management.

Although the precise mechanism is not yet known, recent experimentalresults indicate that the prostaglandin-induced reduction in intraocularpressure results from increased uveoscleral outflow [Nilsson et al.,Invest. Ophthalmol. Vis. Sci. 28(suppl), 284 (1987)].

The isopropyl ester of PGF_(2a) has been shown to have significantlygreater hypotensive potency than the parent compound, which wasattributed to its more effective penetration through the cornea. In 1987this compound was described as “the most potent ocular hypotensive agentever reported.” [See, for example, Bito, L. Z., Arch. Ophthalmol. 105,1036 (1987), and Siebold et al. Prodrug 5, 3 (1989)].

Whereas prostaglandins appear to be devoid of significant intraocularside effects, ocular surface (conjunctival) hyperemia and foreign-bodysensation have been consistently associated with the topical ocular useof such compounds, in particular PGF_(2a) and its prodrugs, e.g. its1-isopropyl ester, in humans. The clinical potential of prostaglandinsin the management of conditions associated with increased ocularpressure, e.g. glaucoma, is greatly limited by these side effects.

Certain phenyl and phenoxy mono, tri and tetra nor prostaglandins andtheir 1-esters are disclosed in European Patent Application 0,364,417 asuseful in the treatment of glaucoma or ocular hypertension.

In a series of United States patent applications assigned to Allergan,Inc. prostaglandin esters with increased ocular hypotensive activityaccompanied with no or substantially reduced side-effects are disclosed.U.S. patent application Ser. No. 386,835 (filed 27 Jul. 1989), relatesto certain 11-acyl-prostaglandins, such as 11-pivaloyl, 11-acetyl,11-isobutyryl, 11-valeryl, and 11-isovaleryl PGF_(2a). Intraocularpressure reducing 15-acyl prostaglandins are disclosed in 3 U.S. Ser.No. 357,394 (filed 25 May 1989). Similarly, 11,15-9,15- and9,11-diesters of prostaglandins, for example 11,15-dipivaloyl PGF_(2a)are known to have ocular hypotensive activity. See U.S. Ser. No. 385,645filed 27 Jul. 1990, now U.S. Pat. No. 4,494,274; 584,370 which is acontinuation of U.S. Ser. No. 386,312, and U.S. Ser. No. 585,284, nowU.S. Pat. No. 5,034,413 which is a continuation of U.S. Ser. No.386,834, where the parent applications were filed on 27 Jul. 1989. Thedisclosures of these patent applications are hereby expresslyincorporated by reference.

Woodward et al U.S. Pat. No. 5,688,819 discloses certain cyclopentaneheptanoic acid, 2-cycloalkyl or arylalkyl compounds as ocularhypotensives. These compounds, which can properly be characterized ashypotensive lipids, are effective in treating ocular hypertension. Thedisclosure of this U.S. Patent is hereby expressly incorporated byreference.

Timolol maleate ophthalmic solution, for example, sold under thetrademark TIMOPTIC® by Merck, is a non-selective beta-adrenergicreceptor blocking agent which is indicated in the treatment of elevatedintraocular pressure in patients with ocular hypertension or opera-angleglaucoma.

The hypotensive lipids and timolol maleate, when used alone, areeffective in treating ocular hypertension. Timolol maleate, when used tocontrol ocular hypertension, may produce one or more disadvantageousside effects, such as headache, fatigue and chest pain, and can havedisadvantageous effects on the cardiovascular, digestive, immunologicand nervous systems.

It would be advantageous to provide for effective, preferably enhanced,treatment of ocular hypertension, preferably with reduced side effectsfrom the treatment employed.

SUMMARY OF THE INVENTION

New compositions for and methods of treating ocular hypertension havebeen discovered. The present invention provides for effective treatmentof ocular hypertension often using compositions including reducedconcentrations of active components. Such compositions and methods haveadvantageously been found to be surprisingly effective in treatingocular hypertension and/or to reduce the number and/or frequency and/orseverity of unwanted side effects caused by timolol components, e.g.,timolol maleate, relative to prior art compositions and methods. Thepresent compositions and methods are relatively straightforward, can beeasily produced, for example, using conventional manufacturingtechniques, and can be easily and conveniently practiced, for example,using application or administration techniques or methodologies whichare substantially similar to those employed with prior compositions usedto treat ocular hypertension.

The present methods of treating ocular hypertension comprise applying toan eye an amount sufficient to treat ocular hypertension of acomposition comprising a timolol component and a hypotensive lipidcomponent. Each of the timolol component and the hypotensive lipidcomponent is present in the composition in an amount effective to reduceocular hypertension when applied to a hypertensive eye, that is an eyewhich has ocular hypertension. The present applying step is effective totreat ocular hypertension, for example, to substantially maintainintraocular pressure or to provide a reduction in intraocular pressure.The present methods preferably provide enhanced treatment of ocularhypertension, for example, enhanced reduction in intraocular pressure,relative to applying a similar composition including either the timololcomponent or the hypotensive lipid component, but not both, at twice theconcentration as in the compositions used in present methods. Thepresent applying step preferably is effective to provide at least onereduced side effect relative to applying a similar composition includingthe timolol component, but not the hypotensive lipid component, toprovide the same treatment of ocular hypertension, e.g., the samereduction in intraocular pressure.

Without wishing to limit the invention to any particular theory or modeof operation, it is believed that the present compositions and methodstake advantage of the different modes of action of the timolol componentand the hypotensive lipid component. For example, the timolol componentalone is effective, when administered to the eye, to decrease the rateof aqueous humor production. On the other hand the hypotensive lipidcomponent alone is effective, when administered to the eye, to increasethe out flow of aqueous humor from the eye. The combination of a timololcomponent and a hypotensive lipid component is believed to provide botha decreased rate of aqueous humor production and an increased aqueoushumor outflow. This combination of active materials is particularlyeffective in treating ocular hypotension in one or more specific groupsof patients, for example, patients with ocular hypotension which,effectively responds to both a reduced rate of aqueous humor productionand an increase in aqueous humor outflow.

The present timolol component/hypotensive lipid component-containingcompositions advantageously provide the same or better reduction inintraocular pressure with reduced concentrations of each of these activematerials relative to similar compositions including only the timololcomponent or the hypotensive component. The reduced concentrations ofthe active materials in the present compositions also reduce the numberand/or severity of side effects, in particular side effects caused bythe timolol component.

The timolol component preferably comprises an acid salt of timolol, morepreferably comprises timolol maleate. The timolol component is presentin the present compositions in an amount effective to reduce intraocularpressure when the composition is applied to a hypertensive eye. Thepreferred amount of timolol component employed is in a range of about0.001% to about 1.0% (w/v), more preferably about 0.01% to about 0.2% orabout 0.25% or about 0.5% (w/v).

In one embodiment, the hypotensive lipid component has the followingformula (I)

wherein the dashed bonds represent a single or double bond which can bein the cis or trans configuration. A is an alkylene or alkenyleneradical having from two to six carbon atoms, which radical may beinterrupted by one or more oxide radicals and substituted with one ormore hydroxy, oxo, alkyloxy or akylcarboxy groups wherein said alkylradical comprises from one to six carbon atoms; B is a cycloalkylradical having from three to seven carbon atoms, or an aryl radical,selected from the group consisting of hydrocarbyl aryl and heteroarylradicals having from four to ten carbon atoms wherein the heteroatom isselected from the group consisting of nitrogen, oxygen and sulfur atoms;X is a radical selected from the group consisting of —OR⁴ and —N(R⁴)₂wherein R⁴ is selected from the group consisting of hydrogen a loweralkyl radical having from one to six carbon atoms,

wherein R⁵ is a lower alkyl radical having from one to six carbon atoms;Z is ═O or represents 2 hydrogen radicals; one of R₁ and R₂ is ═O, —OHor a —O(CO)R₆ group, and the other one is —OH or —O(CO)R₆, or R₁ is ═Oand R₂ is H, wherein R₆ is a saturated or unsaturated acyclichydrocarbon group having from 1 to about 20 carbon atoms, or —(CH₂)mR₇wherein m is 0 or an integer of from 1 to 10, and R₇ is cycloalkylradical, having from three to seven carbon atoms, or a hydrocarbyl arylor heteroaryl radical, as defined above, or apharmaceutically-acceptable salt thereof, provided, however, that when Bis not substituted with a pendant heteroatom-containing radical, and Zis ═O, then X is not —OR⁴. (That is, the cycloalkyl or hydrocarbyl arylor heteroaryl radical is not substituted with a pendant radical havingan atom other than carbon or hydrogen.)

More preferably the hypotensive lipid component has the followingformula II

wherein y is 0 or 1, x is 0 or 1 and x and y are not both 1, Y is aradical selected from the group consisting of alkyl, halo, e.g. fluoro,chloro, etc., nitro, amino, thiol, hydroxy, alkyloxy, alkylcarboxy, halosubstituted alkyl wherein said alkyl radical comprises from one to sixcarbon atoms, etc. and n is 0 or an integer of from 1 to about 3 and R₃is ═O, —OH or —O(CO)R₆ wherein R₆ is as defined above. Preferably, n is1 or 2.

Preferably the hypotensive lipid component has the following formula(III).

wherein hatched lines indicate a configuration, solid triangles are usedto indicate β configuration.

In one embodiment, the hypotensive lipid component has the followingformula (IV)

wherein Y¹ is Cl or trifluoromethyl and the other symbols andsubstituents are as defined above, in combination with a pharmaceuticalcarrier.

In a useful embodiment, the hypotensive lipid component has thefollowing Formula (V)

and the 9-and/or 11- and/or 15 esters thereof.

The hypotensive lipid component is present in the present compositionsin an amount effective to reduce intraocular pressure when thecomposition is applied to a hypertensive eye. The preferred amount ofhypotensive lipid component employed is in a range of about 0.00001% toabout 0.1% (w/v), more preferably about 0.0001% to about 0.01% (w/v).

In a further aspect, the present invention relates to pharmaceuticalcompositions comprising a therapeutically effective amount of a timololcomponent, and a therapeutically effective amount of a hypotensive lipidcomponent of formulae (I), (II), (III), (IV) or (V) wherein the symbolshave the above meanings, or a pharmaceutically acceptable salt thereof,in admixture with a non-toxic, pharmaceutically acceptable liquidvehicle.

Each and every feature described herein, and each and every combinationof two or more of such features, is included within the scope of thepresent invention provided that the features included in such acombination are not mutually inconsistent.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphical representation of certain effects of a hypotensivelipid/timolol maleate combination on intraocular pressure of laserinduced ocular hypertensive cynomolgus monkeys.

FIG. 2 is a graphical representation of certain other effects of ahypotensive lipid/timolol maleate combination on intraocular pressure oflaser induced ocular hypertensive cynomolgus monkeys.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the use of combinations of timololcomponents and lipid hypotensive components as ocular hypotensives inthe treatment of ocular hypertension.

The timolol component is classified as a non-selective beta-adrenergicreceptor blocking agent. The chemical name of timolol maleate, a highlypreferred timolol component in the present invention, is(−)-1-tert-butylamino)-3-[(4-morpholino-1,2,5-thiodiazol-3yl)oxy]-2-propanolmaleate (1:1) (salt). Other pharmacologically acceptable acid salts maybe employed alone or in combination with or without timolol maleate.However, because of its ready availability and its past, knownusefulness as an ocular hypotensive, timolol maleate is preferred foruse in the present invention. Timolol maleate possesses an asymmetriccarbon atom in its structure and preferably is provided as thelevo-isomer.

The preferred amount of timolol component employed is in the range ofabout 0.001% to about 1.0% (w/v), more preferably about 0.0005% or about0.01% to about 0.2% or about 0.25% or about 0.5% (w/v), based on theamount of timolol present. To illustrate, each mL of a solutioncontaining 0.25% (w/v) contains 2.5 mg of timolol (3.4 mg of timololmaleate).

Currently, Merck sells ophthalmic solutions of timolol maleate (undertrademark TIMOPTIC® in concentrations of 0.25% (w/v) and 0.5% (w/v). Thepresent compositions and methods preferably employ concentrations oftimolol component which are reduced relative to these commerciallyavailable materials. It has been surprisingly found that fullyacceptable levels of ocular hypertension treatment are achieved withthese reduced concentrations of timolol component in combination withthe presently useful hypotensive lipid components, also preferablypresent at relatively reduced concentrations. The reduced amounts ofboth timolol component and hypotensive lipid component have surprisinglybeen found to provide enhanced reduction in intraocular pressure whenapplied to a hypertensive eye relative to applying a similar compositioncontaining twice as much of one, but not both, of the timolol componentand the hypotensive lipid component to the hypertensive eye. Therelatively reduced amounts of timolol component and hypertensive lipidcomponent advantageously provide at least one reduced side effect whenapplied to an eye relative to applying a similar composition includingone, but not both, of the timolol component and the hypotensive lipidcomponent to an eye to get the same degree of ocular hypotensiontreatment, for example, the same degree of reduction of intraocularpressure.

The hypotensive lipid components useful in the present invention arecyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl compounds. Thesehypotensive lipid components are represented by compounds having theformula I,

as defined above. The preferred nonacidic hypotensive lipid componentsused in accordance with the present invention have the following formula(II)

wherein the substituents and symbols are as hereinabove defined. Morepreferably the hypotensive lipid components have the following formula(III)

wherein the substituents and symbols are as defined above. Morepreferably, the hypotensive lipid components utilized in the presentinvention have the following formula (IV)

wherein the substituents and the symbols are as defined above.

Still more preferably the present invention utilizes the hypotensivelipid compounds having the following formula (V)

and their 9- and/or and/or 15-esters.

In all of the above formulae (I) to (V) for the hypotensive lipidcomponents, as well as in those provided hereinafter, the dotted lineson bonds between carbons 5 and 6 (C-5), between carbons is and 14(C-13), between carbons 8 and 12 (C-8), and between carbons 10 and 11(C-10) indicate a single or a double bond which can be in the cis ortrans configuration. If two solid lines are used that indicates aspecific configuration for that double bond. Hatched lines at positionsC-9, C-11 and C-15 indicate the α configuration. If one were to draw theβ configuration, a solid triangular line would be used.

In the hypotensive lipid components used in accordance with the presentinvention, compounds having the C-9 or C-11 or C-15 substituents in theα or β configuration are contemplated. As hereinabove mentioned, in allformulas provided herein broken line attachments to the cyclopentanering indicate substituents in the a configuration. Thickened solid lineattachments to the cyclopentane ring indicate substituents in the βconfiguration. Also, the broken line attachment of the hydroxyl group orother substituent to the C-11 and C-15 carbon atoms signifies the αconfiguration.

For the purpose of this invention, unless further limited, the term“alkyl” refers to alkyl groups having from one to about ten carbonatoms, the term “cycloalkyl” refers to cycloalkyl groups having fromthree to about seven carbon atoms, the term “aryl” refers to aryl groupshaving from four to about ten carbon atoms. The term “saturated orunsaturated acyclic hydrocarbon group” is used to refer to straight orbranched chain, saturated or unsaturated hydrocarbon groups having fromone to about 6, preferably one to about 4 carbon atoms. Such groupsinclude alkyl, alkenyl and alkynyl groups of appropriate lengths, andpreferably are alkyl, e.g. methyl, ethyl, propyl, butyl, pentyl, orhexyl, or an isomeric form thereof.

The definition of R₆ may include a cyclic component, —(CH₂)_(m)R₇,wherein m is O or an integer of from 1 to 10, R₇ is an aliphatic ringfrom about 3 to about 7 carbon atoms, or an aromatic or heteroaromaticring. The “aliphatic ring” may be saturated or unsaturated, andpreferably is a saturated ring having 3-7 carbon atoms, inclusive. As anaromatic ring, R₇ preferably is phenyl, and the heteroaromatic ringshave oxygen, nitrogen or sulfur as a heteroatom, i.e. R₇ may be thienyl,furanyl, pyridyl, etc. Preferably m is 0 or an integer of from 1 to 4.

Z is ═O or represents two hydrogen atoms.

X may be selected from the group consisting of —OR⁴ and —N(R⁴)₂ whereinR⁴ is selected from the group consisting of hydrogen, a lower alkylradical having from one to six carbon atoms,

wherein R⁵ is a lower alkyl radical having from one to six carbon atoms.

Preferred representatives of the hypotensive lipid components within thescope of the present invention are the compounds of formula V wherein Xis —OH, i.e. cyclopentane heptenoic acid,5-cis-2-(3-αhydroxy-4-m-chlorophenoxy-1-trans-butenyl)-3,5-dihydroxy,[1α,2β,3α, 5α] and cyclopentanemethylheptenoate-5-cis-2-(3-αhydroxy-4-m-chlorophenoxy-1-trans-butenyl)-3,5dihydroxy, [1α, 2β,3α,5α] and the 9- and/or 11- and/or 15-esters of thiscompound. (The numbered designations in brackets refer to the positionson the cyclopentane ring.)

The following hypotensive lipid components may be used in thepharmaceutical compositions and the methods of the present invention.

(1) cyclopentaneheptenol-5-cis-2-(3α-hydroxy-5-phenyl-1-trans-pentenyl)-3,5-dihydroxy,[1α,2β,3α,5α]

(2) cyclopentaneheptenamide-5-cis-2-(3α-hydroxy-5-phenyl-1-trans-pentenyl)-35-dihydroxy, [1α,2β,3α,5α]

(3) cyclopentaneN,N-dimethylheptenamide-5-cis-2-(3α-hydroxy-5-phenyl-1-trans-pentenyl)-3,5-dihydroxy,[1α,2β,3α,5α]

(4) cyclopentane heptenylmethoxide-5-cis-2-(3α-hydroxy-5-phenyl-1-trans-pentenyl)-3,5-dihydroxy,[1α,2β,3α,5α]

(5) cyclopentane heptenylethoxide-5-cis-2-(3α-hydroxy-4-meta-chlorophenoxy-1-trans-pentenyl)-3,5-dihydroxy,[1α,2β,3α,5α]

(6) cyclopentaneheptenylamide-5-cis-2-(3α-hydroxy-4-meta-chlorophenoxy-1-trans-pentenyl)-3,5-dihydroxy,[1α,2β,3α,5α]

(7) cyclopentaneheptenylamide-5-cis-2-(3α-hydroxy-4-trifluoromethylphenoxy-1-trans-pentenyl)-3,5-dihydroxy,[1α,2β,3α,5α]

(8) cyclopentane N-isopropylheptenamide-5-cis-2-(3α-hydroxy-5-phenyl-1-trans-pentenyl)-3,5-dihydroxy,[1α,2β,3α,5α]

(9) cyclopentane N-ethylheptenamide-5-cis-2-(3α-hydroxy-5-phenyl-1-trans-pentenyl)-3,5dihydroxy, [1α,2β,3α,5α]

(10) cyclopentane N-methylheptenamide-5-cis-2-(3α-hydroxy-5-phenyl-1-trans-pentenyl)-3,5-dihydroxy,[1α,2β,3α,5α]

(11) cyclopentaneheptenol-5-cis-2-(3α-hydroxy-4-meta-chlorophenoxy-1-trans-butenyl)-3,5-dihydroxy,[1α,2β,3α,5α]

(12) cyclopentaneheptenamide-5-cis-2-(3α-hydroxy-4-meta-chlorophenoxy-1-trans-butenyl)-5-dihydroxy,[1α,2β,3α,5α]

(13) cyclopentaneheptenol-5-cis-2-(3α-hydroxy-5-phenyl-1-trans-pentenyl)3,5-dihydroxy,[1α,2β,3α,5α]

A pharmaceutically acceptable salt is any salt which retains theactivity of the parent compound and does not impart any deleterious orundesirable effect on the subject to whom it is administered and in thecontext in which it is administered. With regard to the hypotensivelipid components, such salts are those formed with pharmaceuticallyacceptable cations, e.g., alkali metals, alkali earth metals, etc.

The hypotensive lipid components are present in the present compositionsin amounts effective to reduce the intraocular pressure of ahypertensive eye to which the composition is applied. Because of thepresence of the active timolol component, the amount of hypotensivelipid component employed preferably is relatively reduced, for example,relative to a composition in which the hypotensive lipid component isthe only ocular hypotensive with the same intraocular pressure reductionbeing achieved. Such reduced amounts of hypotensive lipid componentsutilized in accordance with the present invention preferably provide areduction in at least one side effect caused by the presence of thehypotensive lipid component. The preferred amount hypotensive lipidcomponent employed is in the range of about 0.00005% to about 1.0%(w/v), more preferably about 0.0001% to about 0.01% or about 0.1% orabout 0.5% (w/v).

Pharmaceutical compositions may be prepared by combining an effectiveamount of each of a timolol component and a hypotensive lipid component,as active ingredients, with conventional ophthalmically acceptablepharmaceutical excipients, and by preparation of unit dosage formssuitable for topical ocular use.

For ophthalmic application, preferably solutions are prepared using aphysiological saline solution as a major vehicle. The pH of suchophthalmic solutions preferably is maintained between about 4.5 andabout 8.0 with an appropriate buffer system, a substantially neutral pHbeing more preferred but not essential. The formulations may alsocontain conventional, pharmaceutically acceptable preservatives,stabilizers, surfactants and one or more other conventionally usedcomponents.

Preferred preservatives that may be used in the pharmaceuticalcompositions of the present invention include, but are not limited tobenzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetatephenylmercuric nitrate, chlorite components, such as stabilized chlorinedioxide, and the like and mixture thereof. A preferred surfactant is,for example, Tween 80. Likewise, various preferred vehicles may be usedin the ophthalmic preparations of the present invention. These vehiclesinclude, but are not limited to, polyvinyl alcohol, povidone (polyvinylpyrrolidone), hydroxypropyl methyl cellulose, poloxamers, carboxymethylcellulose, hydroxyethyl cellulose, cyclodextrin and purified water andcombinations or mixtures thereof.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers, boratebuffers and the like and mixtures thereof. Acids or bases may be used toadjust the pH of these formulations as needed.

In a similar vein, an ophthalmically acceptable antioxidant componentmay be included in the present composition. Such antioxidant componentsinclude, but are not limited to, sodium metabisulfite, sodiumthiosulfate, acetylcysteine, butylated hydroxyanisole, butylatedhydroxytoluene, and the like and mixtures thereof.

Other excipient components which may be included in the ophthalmicpreparations include, without limitation, chelating agents. Thepreferred chelating agent is EDTA disodium, although other chelatingagents may be used in place of or in conjunction with it.

The ingredients are usually an the following amounts:

Ingredients Amount (w/%) Timolol Component about 0.001-1 HypotensiveLipid Component about 0.00005-1 eservative   0-0.10 Vehicle   0-40Tonicity adjustor   0-10 Buffer 0.01-10 pH adjustor q.s. pH 4.5-7.5antioxidant as needed surfactant as needed purified water as needed tomake 100%

The actual doses of the timolol component and hypotensive lipidcomponent used depends on the specific compounds, being employed on thespecific condition suiting in the ocular hypertension being treated, onthe severity and duration of the ocular hypertension being treated, andthe like factors. In general, the selection of the appropriate doses iswell within the knowledge of the skilled artisan.

The ophthalmic formulations of the present invention are convenientlypackaged in forms suitable for metered application, such as incontainers equipped with a dropper, to facilitate application to theeye. Containers suitable for dropwise application are usually made ofsuitable inert, non-toxic plastic material, and generally containbetween about 0.5 and about 15 ml solution. One package may contain oneor more unit doses.

Especially preservative-free solutions are often formulated innon-resealable containers containing up to about ten, preferably up toabout five units doses, where a typical unit dose is in the range of oneto about 8 drops, preferably one to about 3 drops. The volume of onedrop usually is about 20-35 ul (microliters).

The invention is further illustrated by the following non-limitingExamples.

EXAMPLES

Intraocular pressure studies were performed in conscious cynomolgusmonkeys, trained to accept pneumatonometry. The animals were restrainedfor pneumatonometry in custom-designed chairs and given fruit during theexperiment.

A series of four (4) compositions were prepared, by blending theingredients together. These compositions were as follows:

Compositions (A) Ingredient 1 2 3 4 Hypotensive lipid (B) 0.001 (w/v) —0.001% (w/v) — Timolol Maleate — 0.05% w/v 0.005% (w/v) — Polysorbate 80 0.01 (w/v)  0.1% (w/v)  0.1% (w/v) 0.1% (w/v) Tris Hcl 10 mM 10 mM 10mM 10 mM

-   -   A. Each composition had a pH of about 7.4 and was an aqueous        solution including 0.9% (w/v) of sodium chloride.    -   B. The hypotensive lipid was: cyclopentane N-ethyl        heptenamide-5-cis-2-(3α-hydroxy-5-phenyl-1-trans-pentenyl)-3,5-dihydroxy,        [1α,2β,3α,4α].

The treatments, coded to the experimeter, were applied topically to theglaucomatous eye as a single 25 μl volume drop, and the normotensivefellow eye received 25 μl of normal saline. The solutions wereadministered at time 0. Proparacaine (0.1%) was used to provide cornealanesthesia for the intraocular pressure measurements that were performedat one hour before dosing, just before dosing, and then 1, 2, 4 and 6hours thereafter.

The mean intraocular pressure (IOP) values for the glaucomatuous eyes attime 0 were 40.5 mm Hg for the Composition 1 group, 38.8 mm Hg for theComposition 2 group, 40.6 mm Hg for the Composition 3 group and 39.5 mmHg for the Composition 4 group.

IOP mean differences from baseline (DFB) for treated eyes (test DFB) andfellow eyes (fellow DFB) are depicted in FIG. 1. Test DFB values werestatistically significant for the following groups (Student's t-test forpaired samples):

Compositions Range (mm Hg), p < 0.05 1 −2.0 to −10.3 2 +2.1 to −13.4 3+2.0 to −19.0 4 +1.0 to −2.3

The effects of combination treatment with the hypotensive lipid and thetimolol component (Composition 3) on IOP of glaucomatous monkeys werecompared to each of the other treatments alone (Student's t-test forunpaired samples, p<0.05). The delta-delta values (test DFB—fellow DFB)for the combination treatment (Composition 3) group were significantlylower than those for the hypotensive lipid alone (composition 1)(time=1, 2 4, 6 hr). The delta-delta values are depicted in FIG. 2.

The combination treatment (Composition 3) using relatively low doses ofhypotensive lipid and timolol maleate was surprisingly found to be moreefficacious in reducing IOP than treatments with either only one ofthese materials (Compositions 1 and 2) or none of these materials(Composition 4).

While this invention has been described with respect to various specificexamples and embodiments, it is to be understood that the invention isnot limited thereto and that it can be variously practiced within thescope of the following claims.

1-33. (canceled)
 34. A first composition for the treatment of glaucomaor ocular hypertension and suitable for administration to an eye, thefirst composition comprising about 0.5% (w/v) timolol and about 0.03%(w/v) bimatoprost in a single composition, wherein the first compositionproduces at least one reduced side effect relative to a secondcomposition comprising the same amount of bimatoprost without timolol.35. The composition of claim 34, wherein the first composition furthercomprises benzalkonium chloride.
 36. The composition of claim 34,wherein the first composition further comprises a citrate buffer and aphosphate buffer.
 37. The composition of claim 34, wherein the reducedside effect is conjunctival hyperemia.
 38. The composition of claim 34,wherein the first composition comprises 0.5% (w/v) timolol, 0.03% (w/v)bimatoprost, and benzalkonium chloride.
 39. The composition of claim 38,wherein the first composition further comprises a citrate buffer, aphosphate buffer, and has a pH of about 7.3.
 40. An aqueous compositionsuitable for ocular administration, the composition comprising 0.68%(w/v) timoloi maleate, 0.03% (w/v) bimatoprost, and benzalkoniumchloride in a single composition, wherein the composition is effectivein reducing intraocular pressure when applied to an eye.
 41. Thecomposition of claim 40, wherein administration of the compositionreduces one or more side effects as compared to the administration ofanother composition comprising 0.03% (w/v) bimatoprost without timololmaleate.
 42. The composition of claim 41, wherein the reduced sideeffect is conjunctival hyperemia.
 43. The composition of claim 40,wherein the composition further comprises a citrate buffer, a phosphatebuffer, and has a pH of about 7.3.